Epidermal growth factor receptor (also known as EGFR, ErbB-1 and HER1) is a cell surface receptor of the ErbB family of receptors, a subfamily of four closely related receptor tyrosine kinases, including EGFR (ErbB-1), HER2/c-neu (ErbB-2), Her 3 (ErbB-3) and Her 4 (ErbB-4). Binding of EGFR to a ligand (such as epidermal growth factor (EGF), transforming growth factor a (TGF α), HB-EGF, amphiregulin, betacellulin/BTC, epigen/EPGN, or other) induces receptor dimerization and autophosphorylation of several tyrosine (Y) residues (Y992, Y1045, Y1068, Y1148, and Y1173) in the C-terminal domain of EGFR. This autophosphorylation elicits downstream activation of several signal transduction cascades, including the MAPK, Akt, and JNK pathways, leading to cell migration, adhesion, and cell proliferation.
Mutations, amplifications or misregulations of EGFR or family members are implicated in about 30% of all epithelial cancers. For example, mutations that lead to EGFR overexpression or overactivity have been associated with a number of cancers, including lung cancer, anal cancers, head and neck cancers, and glioblastoma multiforme. The identification of EGFR as an oncogene has led to the need for the development of anticancer therapeutics directed against EGFR. The present invention meets this and other needs.